Neurosci Lett. 2023 Aug 28:137456. doi: 10.1016/j.neulet.2023.137456. Online ahead of print.

ABSTRACT

OBJECTIVE: We evaluated the potential neuro-regenerative effects of the mitochondrial uncoupler 2,4-Dinitrophenol in experimental autoimmune neuritis, an animal model for an acute autoimmune neuropathy.

METHODS: Experimental autoimmune neuritis was induced in Lewis rats. Different concentrations of 2,4-Dinitrophenol (1 mg/kg, 0.1 mg/kg and 0.01 mg/kg) were applied during the recovery phase of the neuritis (at days 18, 22 and 26) and compared to the vehicle. Any effects were assessed through functional, electrophysiological, and morphological analysis via electron microscopy of all groups at day 30. Additional immune-histochemical analysis of inflammation markers and remyelination of the sciatic nerves were performed for the dosage of 1 mg/kg and control.

RESULTS: No enhancement of functional or electrophysiological recovery was observed in all 2,4-Dinitrophenol-treated groups. Cellular inflammation markers of T cells (CD3 + ) were comparable to control, and an increase of macrophages (IbA1 + ) invasion in the sciatic nerves was observed. Treatment with 2,4-Dinitrophenol reduced axonal swelling in myelinated and unmyelinated fibers with an increased production of brain-derived neurotrophic factor.

CONCLUSION: Our findings do not support the hypothesis that repurposing of the mitochondrial uncoupler 2,4-Dinitrophenol exerts functionally relevant neuro-regenerative effects in autoimmune neuritis.

PMID:37648059 | DOI:10.1016/j.neulet.2023.137456

Eur J Cancer. 2023 Aug 6;192:113277. doi: 10.1016/j.ejca.2023.113277. Online ahead of print.

NO ABSTRACT

PMID:37647850 | DOI:10.1016/j.ejca.2023.113277

bioRxiv. 2023 Aug 18:2023.08.18.553822. doi: 10.1101/2023.08.18.553822. Preprint.

ABSTRACT

Host-directed therapy (HDT) is an emerging approach to overcome antimicrobial resistance in pathogenic microorganisms. Specifically, HDT targets host-encoded factors required for pathogen replication and survival without interfering with microbial growth or metabolism, thereby eliminating the risk of resistance development. By applying HDT and a drug repurposing approach, we demonstrate that ( R )-DI-87, a clinical-stage anti-cancer drug and potent inhibitor of mammalian deoxycytidine kinase (dCK), attenuates the virulence of antibiotic-resistant Staphylococcus aureus in a mouse model of bloodstream infection. Mechanistically, ( R )-DI-87 shields phagocytes from staphylococcal death-effector deoxyribonucleosides that target dCK and the mammalian purine salvage pathway-apoptosis axis. In this manner, ( R )-DI-87-mediated protection of immune cells amplifies macrophage infiltration into deep-seated abscesses, a phenomenon coupled with enhanced pathogen control, ameliorated immunopathology, and reduced disease severity. Thus, pharmaceutical blockade of dCK represents an advanced anti-infective intervention strategy against which staphylococci cannot develop resistance and may help to fight fatal infectious diseases in hospitalized patients.

PMID:37645972 | PMC:PMC10462150 | DOI:10.1101/2023.08.18.553822

bioRxiv. 2023 Aug 17:2023.08.15.553422. doi: 10.1101/2023.08.15.553422. Preprint.

ABSTRACT

Hypoxia-inducible-factors (HIF) are transcription factors that regulate cellular adaptation to hypoxic conditions, enabling cells to survive in low-oxygen environments. Viruses have evolved to stabilize this pathway to promote successful viral infection, therefore modulation of HIFs could represent a novel antiviral strategy. In previous in vitro studies, we demonstrate respiratory syncytial virus (RSV), a leading cause of respiratory illness, to stabilize HIFs under normoxic conditions, with inhibition of HIF-1α resulting in reduced viral replication. Despite several HIF modulating compounds being tested/approved for use in other non-infectious models, little is known about their efficacy against respiratory viruses using relevant animal models. This study aimed to characterize the disease modulating properties and antiviral potential of anti-HIF-1α (PX478) and anti-HIF-2α (PT2385) in RSV-infected BALB/c mice. We found inhibition of HIF-1α to worsen clinical disease parameters, while simultaneously improving airway function. Additionally, anti-HIF-1α results in significantly reduced viral titer at early and peak time points of RSV replication, followed by a loss in viral clearance when given every day, but not every-other-day. In contrast, inhibition of HIF-2α was associated with improved clinical parameters, with no changes in airway function, and amelioration of interstitial pneumonia. Furthermore, anti-HIF-2α reduced early and peak lung viral replication, with no impaired viral clearance. Analysis of lung cells found significant modification in the T cell compartment that correlated with changes in lung pathology and viral titers in response to each HIF inhibitor administration. These data underscore the complex role of HIFs in RSV infection and highlight the need for careful therapeutic consideration.

IMPORTANCE: The pharmacological use of HIF therapeutics has largely been investigated with various models of cancer, autoimmunity, and non-infectious lung damage. The safety and success of these compounds is emphasized by their use in several phase-4 clinical trials. Since the early 2000s, numerous studies have demonstrated the antiviral potential of HIF inhibitors in epithelial cell lines, however, there are no studies characterizing the therapeutic outcomes of suppressing HIF during a viral respiratory infection in a relevant animal model. With the growing interest in drug repositioning, our research emphasizes the importance of testing approved or abandoned therapeutics under the new conditions in a complex biological model encompassing both the epithelial and immune compartments. Moreover, the current study uncovers a novel role of HIFs in the pathogenesis of RSV disease. These data collectively demonstrate a key mechanism in immune regulation during RSV infection that can further therapeutic development.

PMID:37645750 | PMC:PMC10461990 | DOI:10.1101/2023.08.15.553422

Front Med (Lausanne). 2023 Aug 14;10:1202504. doi: 10.3389/fmed.2023.1202504. eCollection 2023.

ABSTRACT

The wide and rapid spread of the COVID-19 pandemic has placed an unanticipated burden on the global healthcare sector. This necessitated a swift response from the international community to reach a solution. Efforts were made in parallel to develop preventative and therapeutic modalities. Since then, drug repurposing has blossomed as a potentially rapid resolution and has included various agents with anti-viral and anti-inflammatory properties. Corticosteroids, being potent anti-inflammatory agents, have been placed under extensive investigation. Various trials have recorded the beneficial outcome of corticosteroids in decreasing the mortality and morbidity of COVID-19. With the high pace of escalating events, the quality and study design of clinical trials are varied. Therefore, this study aims to explore the role of corticosteroids in COVID-19 disease. It inspects the molecular, pharmacologic, and clinical proof behind this theory.

PMID:37644981 | PMC:PMC10461317 | DOI:10.3389/fmed.2023.1202504

J Biomol Struct Dyn. 2023 Aug 29:1-14. doi: 10.1080/07391102.2023.2252072. Online ahead of print.

ABSTRACT

Human adenovirus (HADV) infection can pose a serious threat to children, leading to a variety of respiratory illnesses and other complications. Particularly, children with weak immune systems are vulnerable to severe adenovirus infections with high mortality. The main focus of this study is to propose new antiviral agents as lead HADV inhibitors for children. So, several antiviral agents used in children were subjected to finding new HADV inhibitors using important computational methods of molecular docking, molecular dynamics (MD) simulation, Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) binding free energy calculations, density functional theory (DFT), and pharmacokinetic analysis. Molecular docking of standard cidofovir along with other ligands, suggested that sofosbuvir has the highest binding energy (-10.8 kcal/mol), followed by baloxavir marboxil (-10.36 kcal/mol). Further, the analysis of molecular interactions using MD simulation (100 ns) and MM-PBSA indicated that baloxavir marboxil has formed the most stable protein-ligand complex with HADV, followed by sofosbuvir. The binding free energies of baloxavir marboxil and sofosbuvir were found to be -61.724 kJ/mol and -48.123 kJ/mol, respectively. The DFT and drug-likeness properties of these compounds were also investigated. Overall, two antiviral agents, such as baloxavir marboxil, and sofosbuvir are suggested as lead repurposed candidates against HADV.Communicated by Ramaswamy H. Sarma.

PMID:37642990 | DOI:10.1080/07391102.2023.2252072

Front Pharmacol. 2023 Aug 10;14:1227330. doi: 10.3389/fphar.2023.1227330. eCollection 2023.

ABSTRACT

Introduction: Cancer registries and hospital electronic medical records are commonly used to investigate drug repurposing candidates for cancer. However, administrative data are often more accessible than data from cancer registries and medical records. Therefore, we evaluated if administrative data could be used to evaluate drug repurposing for cancer by conducting an example study on the association between beta-blocker use and breast cancer mortality. Methods: A retrospective cohort study of women aged ≥50 years with incident breast cancer was conducted using a linked dataset with statewide hospital admission data and nationwide medication claims data. Women receiving beta blockers and first-line anti-hypertensives prior to and at diagnosis were compared. Breast cancer molecular subtypes and metastasis status were inferred by algorithms from commonly prescribed breast cancer antineoplastics and hospitalization diagnosis codes, respectively. Subdistribution hazard ratios (sHR) and corresponding 95% confidence intervals (CIs) for breast cancer mortality were estimated using Fine and Gray's competing risk models adjusted for age, Charlson comorbidity index, congestive heart failure, myocardial infraction, molecular subtype, presence of metastasis at diagnosis, and breast cancer surgery. Results: 2,758 women were hospitalized for incident breast cancer. 604 received beta-blockers and 1,387 received first-line antihypertensives. In total, 154 breast cancer deaths were identified over a median follow-up time of 2.7 years. We found no significant association between use of any beta-blocker and breast-cancer mortality (sHR 0.86, 95%CI 0.58-1.28), or when stratified by beta-blocker type (non-selective, sHR 0.42, 95%CI 0.14-1.25; selective, sHR 0.95, 95%CI 0.63-1.43). Results were not significant when stratified by molecular subtypes (e.g., triple negative breast cancer (TNBC), any beta blocker, sHR 0.16, 95%CI 0.02-1.51). Discussion: It is possible to use administrative data to explore drug repurposing opportunities. Although non-significant, an indication of an association was found for the TNBC subtype, which aligns with previous studies using registry data. Future studies with larger sample size, longer follow-up are required to confirm the association, and linkage to clinical data sources are required to validate our methodologies.

PMID:37637417 | PMC:PMC10448902 | DOI:10.3389/fphar.2023.1227330

RSC Adv. 2023 Aug 24;13(36):25218-25228. doi: 10.1039/d3ra03796g. eCollection 2023 Aug 21.

ABSTRACT

Artificial intelligence has become more prevalent in broad fields, including drug discovery, in which the process is costly and time-consuming when conducted through wet experiments. As a result, drug repurposing, which tries to utilize approved and low-risk drugs for a new purpose, becomes more attractive. However, screening candidates from many drugs for specific protein targets is still expensive and tedious. This study aims to leverage computational resources to aid drug discovery by utilizing drug-protein interaction data and estimating their interaction strength, so-called binding affinity. Our estimation approach addresses multiple challenges encountered in the field. First, we employed a graph-based deep learning technique to overcome the limitations of drug compounds represented in string format by incorporating background knowledge of node and edge information as separate multi-dimensional features. Second, we tackled the complexities associated with extracting the representation and structure of proteins by utilizing a pre-trained model for feature extraction. Also, we employed graph operations over the 1D representation of a protein sequence to overcome the fixed-length problem typically encountered in language model tasks. In addition, we conducted a comparative analysis with a baseline model that creates a protein graph from a contact map prediction model, giving valuable insights into the performance and effectiveness of our proposed method. We evaluated the performance of our model using the same benchmark datasets with a variety of matrices as other previous work, and the results show that our model achieved the best prediction results while requiring no contact map information compared to other graph-based methods.

PMID:37636509 | PMC:PMC10448119 | DOI:10.1039/d3ra03796g

Colorectal Dis. 2023 Aug 27. doi: 10.1111/codi.16724. Online ahead of print.

ABSTRACT

AIM: Inflammatory cells within the tumour microenvironment are the driving forces behind colorectal cancer (CRC) tumourigenesis. Understanding the different pathways involved in CRC carcinogenesis paves the way for effective repurposing of drugs for cancer prevention. Emerging data from preclinical and clinical studies suggest that, due to their antiproliferative and anti-inflammatory properties, phosphodiesterase-5 inhibitors (PDE5i) might have an anticancer effect. The aim of this study was to clarify through systematic review and meta-analysis of published peer-reviewed studies whether an association exists between PDE5i use and CRC risk.

METHOD: This study was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Prospective registration was performed on PROSPERO (CRD42022372925). A systematic review was performed for studies reporting CRC and advanced colorectal polyp incidence in PDE5i 'ever-users' and PDE5i 'never-users'. Meta-analysis was performed using RevMan version 5.

RESULTS: Four observational cohort studies and two case-control studies, comprising 995 242 patients were included in the final analysis, of whom 347 126 were PDE5i ever-users. Patients who were PDE5i ever-users had a significantly lower incidence of CRC or advanced colorectal polyps than never-users (OR 0.88, CI 0.79-0.98, p = 0.02). To examine the primary preventative role of PDE5i, subgroup analysis of four studies including patients without a previous history of CRC found that use of PDE5i was associated with a lower incidence of CRC (OR 0.85, CI 0.75-0.95, p = 0.005, I2 = 64%). There was no significant temporal relationship found between PDE5i use and CRC risk as both current users and previous users had a significantly lower incidence of CRC than never-users.

CONCLUSION: Our study found a significant anticancer effect of PDE5i, as shown by a reduced risk of CRC in the context of both primary and secondary CRC prevention.

PMID:37635321 | DOI:10.1111/codi.16724

Biochem Pharmacol. 2023 Aug 25:115766. doi: 10.1016/j.bcp.2023.115766. Online ahead of print.

ABSTRACT

Trypanosoma cruzi is the causative agent of Chagas' disease, an endemic and neglected disease. The treatment is limited to only two drugs, benznidazole (BZL) and nifurtimox (NFX), introduced more than fifty years ago and no new advances have been made since then. Nucleoside diphosphate kinases (NDPK) are key metabolic enzymes which have gained interest as drug targets of pathogen organisms. Taking advantage of the computer-assisted drug repurposing approaches, in the present work we initiate a search of potential T. cruzi nucleoside diphosphate kinase 1 (TcNDPK1) inhibitors over an ∼12,000 compound structures database to find drugs targeted to this enzyme with trypanocidal activity. Four medicines were selected and evaluated in vitro, ketorolac (KET, an anti-inflamatory), dutasteride (DUT, used to treat benign prostatic hyperplasia), nebivolol and telmisartan (NEB and TEL, used to treat high blood pressure). The four compounds were weak inhibitors and presented different trypanocidal effect on epimastigotes, trypomastigotes and intracellular stages. NEB and TEL were the most active drugs with increased effect on intracellular stages, (IC50=2.25 µM and 13.21 µM respectively), and selectivity indexes of 13.01 and 8.59 respectively, showing comparable effect to BZL, the first line drug for Chagas' disease treatment. In addition, both presented positive interactions when combined with BZL. Finally, transgenic epimastigotes with increased expression of TcNDPK1 were more resistant to TEL and NEB, suggesting that TcNDPK1 is at least one of the molecular targets. In view of the results, NEB and TEL could be repurposed medicines for Chagas' disease therapy.

PMID:37634596 | DOI:10.1016/j.bcp.2023.115766

EBioMedicine. 2023 Aug 24;95:104767. doi: 10.1016/j.ebiom.2023.104767. Online ahead of print.

ABSTRACT

BACKGROUND: Although Deep Neural Networks (DDNs) have been successful in predicting the efficacy of cancer drugs, the lack of explainability in their decision-making process is a significant challenge. Previous research proposed mimicking the Gene Ontology structure to allow for interpretation of each neuron in the network. However, these previous approaches require huge amount of GPU resources and hinder its extension to genome-wide models.

METHODS: We developed SparseGO, a sparse and interpretable neural network, for predicting drug response in cancer cell lines and their Mechanism of Action (MoA). To ensure model generalization, we trained it on multiple datasets and evaluated its performance using three cross-validation schemes. Its efficiency allows it to be used with gene expression. In addition, SparseGO integrates an eXplainable Artificial Intelligence (XAI) technique, DeepLIFT, with Support Vector Machines to computationally discover the MoA of drugs.

FINDINGS: SparseGO's sparse implementation significantly reduced GPU memory usage and training speed compared to other methods, allowing it to process gene expression instead of mutations as input data. SparseGO using expression improved the accuracy and enabled its use on drug repositioning. Furthermore, gene expression allows the prediction of MoA using 265 drugs to train it. It was validated on understudied drugs such as parbendazole and PD153035.

INTERPRETATION: SparseGO is an effective XAI method for predicting, but more importantly, understanding drug response.

FUNDING: The Accelerator Award Programme funded by Cancer Research UK [C355/A26819], Fundación Científica de la AECC and Fondazione AIRC, Project PIBA_2020_1_0055 funded by the Basque Government and the Synlethal Project (RETOS Investigacion, Spanish Government).

PMID:37633093 | DOI:10.1016/j.ebiom.2023.104767

Bioinformatics. 2023 Aug 26:btad529. doi: 10.1093/bioinformatics/btad529. Online ahead of print.

ABSTRACT

MOTIVATION: Model organisms are widely used to better understand the molecular causes of human disease. While sequence similarity greatly aids this transfer, sequence similarity does not imply functional similarity, and thus, several current approaches incorporate protein-protein interactions (PPIs) to help map findings between species. Existing transfer methods either formulate the alignment problem as a matching problem which pits network features against known orthology, or more recently, as a joint embedding problem.

RESULTS: We propose a novel state-of-the-art joint embedding solution: Embeddings to Network Alignment (ETNA). ETNA generates individual network embeddings based on network topological structures and then uses a Natural Language Processing-inspired cross-training approach to align the two embeddings using sequence-based orthologs. The final embedding preserves both within and between species gene functional relationships, and we demonstrate that it captures both pairwise and group functional relevance. In addition, ETNA's embeddings can be used to transfer genetic interactions across species and identify phenotypic alignments, laying the groundwork for potential opportunities for drug repurposing and translational studies.

AVAILABILITY: https://github.com/ylaboratory/ETNA.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID:37632792 | DOI:10.1093/bioinformatics/btad529

Neurochem Res. 2023 Aug 26. doi: 10.1007/s11064-023-04019-2. Online ahead of print.

ABSTRACT

Parkinson's Disease (PD) is caused by many factors and endoplasmic reticulum (ER) stress is considered as one of the responsible factors for it. ER stress induces the activation of the ubiquitin-proteasome system to degrade unfolded proteins and suppress cell death. The ubiquitin ligase 3-hydroxy-3-methylglutaryl-coenzyme A reductase degradation 1 (HRD1) and its stabilizing molecule, the suppressor/enhancer lin-12-like (SEL1L), can suppress the ER stress via the ubiquitin-proteasome system, and that HRD1 can also suppress cell death in familial and nonfamilial PD models. These findings indicate that HRD1 and SEL1L might be key proteins for the treatment of PD. Our study aimed to identify the compounds with the effects of upregulating the HRD1 expression and suppressing neuronal cell death in a 6-hydroxydopamine (6-OHDA)-induced cellular PD model. Our screening by the Drug Gene Budger, a drug repositioning tool, identified luteolin as a candidate compound for the desired modulation of the HRD1 expression. Subsequently, we confirmed that low concentrations of luteolin did not show cytotoxicity in SH-SY5Y cells, and used these low concentrations in the subsequent experiments. Next, we demonsrated that luteolin increased HRD1 and SEL1L mRNA levels and protein expressions. Furthermore, luteolin inhibited 6-OHDA-induced cell death and suppressed ER stress response caused by exposure to 6-OHDA. Finally, luteolin did not reppress 6-OHDA-induced cell death when expression of HRD1 or SEL1L was suppressed by RNA interference. These findings suggest that luteolin might be a novel therapeutic agent for PD due to its ability to suppress ER stress through the activation of HRD1 and SEL1L.

PMID:37632637 | DOI:10.1007/s11064-023-04019-2

Mol Divers. 2023 Aug 26. doi: 10.1007/s11030-023-10716-5. Online ahead of print.

ABSTRACT

Dengue is an emerging, mosquito-borne viral disease of international public health concern. Dengue is endemic in more than 100 countries across the world. However, there are no clinically approved antivirals for its cure. Drug repurposing proves to be an efficient alternative to conventional drug discovery approaches in this regard, as approved drugs with an established safety profile are tested for new indications, which circumvents several time-consuming experiments. In the present study, eight approved RNA-dependent RNA polymerase inhibitors of Hepatitis C virus were virtually screened against the Dengue virus polymerase protein, and their antiviral activity was assessed in vitro. Schrödinger software was used for in silico screening, where the compounds were passed through several hierarchical filters. Among the eight compounds, dasabuvir was finally selected for in vitro cytotoxicity and antiviral screening. Cytotoxicity profiling of dasabuvir in Vero cells revealed changes in cellular morphology, cell aggregation, and detachment at 50 μM. Based on these results, four noncytotoxic concentrations of dasabuvir (0.1, 0.25, 0.5, and 1 µM) were selected for antiviral screening against DENV-2 under three experimental conditions: pre-infection, co-infection, and post-infection treatment, by plaque reduction assay. Viral plaques were reduced significantly (p < 0.05) in the co-infection and post-infection treatment regimens; however, no reduction was observed in the pretreatment group. This indicated a possible interference of dasabuvir with NS5 RdRp, as seen from in silico interaction studies, translating into a reduction in virus plaques. Such studies reiterate the usefulness of drug repurposing as a viable strategy in antiviral drug discovery. In this drug repurposing study, dasabuvir, a known anti-hepatitis C drug, was selected through virtual screening and assessed for its anti-dengue activity.

PMID:37632595 | DOI:10.1007/s11030-023-10716-5

J Biomol Struct Dyn. 2023 Aug 26:1-11. doi: 10.1080/07391102.2023.2251070. Online ahead of print.

ABSTRACT

The protein kinase Wee1 plays a vital role in the G2/M cell cycle checkpoint activation, triggered by double-stranded DNA disruptions. It fulfills this task by phosphorylating and consequently deactivating the cyclin B linked to Cdk1/Cdc2 at the Tyr15 residue, leading to a G2 cell cycle halt and subsequent delay of mitosis post DNA damage. Despite advancements, only the Wee1 inhibitor MK1775 has made it to Phase II clinical trials, presenting a challenge in innovative chemical structure development for small molecule discovery. To navigate this challenge, we employed an e-pharmacophore model of the MK1775-WEE1 complex (PDB ID: 5V5Y), using in silico screening of FDA-approved drugs. We chose six drugs for analog creation, guided by docking scores, key residue interactions, and ligand occupancy. Utilizing the 'DrugSpaceX' database, we generated 2,776 analogues via expert-defined transformations. Our findings identified DE90612 as the top-ranked analogue, followed by DE363106, DE489678, DE395383, DE90548, DE689343, DE395019, and DE538066. These analogues introduced unique structures not found in other databases. A t-SNE structurally diversified distribution map unveiled promising transformations linked to Temozolomide for WEE1 inhibitor development. Simulations of the WEE1-DE90612 complex (a Temozolomide analogue) for 200 nanoseconds demonstrated stability, with DE90612 forging robust bonds with active site residues and sustaining vital contacts at ASN376 and CYS379. These results underscore DE90612's potential inhibitory properties at the WEE1 binding site, warranting additional in vitro and in vivo exploration for its anticancer activity. Our approach outlines a promising pathway for creating diverse WEE1 inhibitors with suitable biological properties for potential oncology therapeutics.Communicated by Ramaswamy H. Sarma.

PMID:37632319 | DOI:10.1080/07391102.2023.2251070

Pharmaceutics. 2023 Aug 21;15(8):2166. doi: 10.3390/pharmaceutics15082166.

ABSTRACT

Immune checkpoint inhibitors (ICI) have achieved unprecedented clinical success in cancer treatment. However, drug resistance to ICI therapy is a major hurdle that prevents cancer patients from responding to the treatment or having durable disease control. Drug repurposing refers to the application of clinically approved drugs, with characterized pharmacological properties and known adverse effect profiles, to new indications. It has also emerged as a promising strategy to overcome drug resistance. In this review, we summarized the latest research about drug repurposing to overcome ICI resistance. Repurposed drugs work by either exerting immunostimulatory activities or abolishing the immunosuppressive tumor microenvironment (TME). Compared to the de novo drug design strategy, they provide novel and affordable treatment options to enhance cancer immunotherapy that can be readily evaluated in the clinic. Biomarkers are exploited to identify the right patient population to benefit from the repurposed drugs and drug combinations. Phenotypic screening of chemical libraries has been conducted to search for T-cell-modifying drugs. Genomics and integrated bioinformatics analysis, artificial intelligence, machine and deep learning approaches are employed to identify novel modulators of the immunosuppressive TME.

PMID:37631380 | DOI:10.3390/pharmaceutics15082166

Pharmaceutics. 2023 Jul 28;15(8):2033. doi: 10.3390/pharmaceutics15082033.

ABSTRACT

This study aims at preparing propranolol-loaded trehalosomes (a trehalose-coated liposome) to be used as an antiproliferative agent for treating skin cancer. A factorial design was used to select the optimum formula, where trehalose, lecithin, and Tween 80 levels were studied. A total of 24 runs were prepared and characterized according to size, charge, entrapment efficiency, and release after 3 h to select the optimum formula. The optimized formula was investigated using TEM, DSC, and FTIR. Cell studies were carried out against the human melanoma cell line to measure cytotoxicity, apoptosis/necrosis, and cell cycle arrest. In silico studies were conducted to understand the interaction between propranolol and the influential receptors in melanoma. The results showed the selected formula consisted of trehalose (175 mg), lecithin (164 mg), and Tween 80 (200 mg) with a size of 245 nm, a charge of -9 mV, an EE% of 68%, and a Q3 of 62%. Moreover, the selected formula has good cytotoxicity compared to the free drug due to the synergistic effect of the drug and the designed carrier. IC50 of free propranolol and the encapsulation of propranolol were 17.48 μg/mL and 7.26 μg/mL, respectively. Also, propranolol and the encapsulation of propranolol were found to significantly increase early and late apoptosis, in addition to inducing G1 phase cell cycle arrest. An in silico virtual study demonstrated that the highest influential receptors in melanoma were the vitamin D receptor, CRH-R1, VEGFR 1, and c-Kit, which matches the results of experimental apoptotic and cell cycle analysis. In conclusion, the selected formula has good cytotoxicity compared to the free drug due to the synergistic effect of the drug and the designed carrier, which make it a good candidate as an antiproliferative agent for treating skin cancer.

PMID:37631247 | DOI:10.3390/pharmaceutics15082033

Pharmaceutics. 2023 Jul 26;15(8):2022. doi: 10.3390/pharmaceutics15082022.

ABSTRACT

Immunotherapy has changed the way many cancers are being treated. Researchers in the field of immunotherapy and tumor immunology are investigating similar questions: How can the positive benefits achieved with immunotherapies be enhanced? Can this be achieved through combinations with other agents and if so, which ones? In our view, there is an urgent need to improve immunotherapy to make further gains in the overall survival for those patients that should benefit from immunotherapy. While numerous different approaches are being considered, our team believes that drug delivery methods along with appropriately selected small-molecule drugs and drug candidates could help reach the goal of doubling the overall survival rate that is seen in some patients that are given immunotherapeutics. This review article is prepared to address how immunotherapies should be combined with a second treatment using an approach that could realize therapeutic gains 10 years from now. For context, an overview of immunotherapy and cancer angiogenesis is provided. The major targets in angiogenesis that have modulatory effects on the tumor microenvironment and immune cells are highlighted. A combination approach that, for us, has the greatest potential for success involves treatments that will normalize the tumor's blood vessel structure and alter the immune microenvironment to support the action of immunotherapeutics. So, this is reviewed as well. Our focus is to provide an insight into some strategies that will engender vascular normalization that may be better than previously described approaches. The potential for drug delivery systems to promote tumor blood vessel normalization is considered.

PMID:37631236 | DOI:10.3390/pharmaceutics15082022

Int J Mol Sci. 2023 Aug 20;24(16):12997. doi: 10.3390/ijms241612997.

ABSTRACT

Drug repositioning (DR) is the process of identifying novel therapeutic potentials for already-approved drugs and discovering new therapies for untreated diseases. DR can play an important role in optimizing the pre-clinical process of developing novel drugs by saving time and cost compared with the process of de novo drug discovery. Although the number of publications related to DR has rapidly increased, most therapeutic approaches were reported for malignant tumors. Surgical resection represents the definitive treatment for benign tumors of the central nervous system (BTCNS). However, treatment options remain limited for surgery-, chemotherapy- and radiation-refractory BTCNS, as well as malignant tumors. Meningioma, pituitary neuroendocrine tumor (PitNET), and schwannoma are the most common BTCNS. The treatment strategy using DR may be applied for refractory BTCNS, such as Grade 2 meningiomas, neurofibromatosis type 2-related schwannomatosis, and PitNETs with cavernous sinus invasion. In the setting of BTCNS, stable disease can provide significant benefit to the patient. DR may provide a longer duration of survival without disease progression for patients with refractory BTCNS. This article reviews the utility of DR for refractory BTCNS.

PMID:37629179 | DOI:10.3390/ijms241612997

Int J Mol Sci. 2023 Aug 9;24(16):12619. doi: 10.3390/ijms241612619.

ABSTRACT

Human carbonic anhydrases (hCAs) have enzymatic activities for reversible hydration of CO2 and are acknowledged as promising targets for the treatment of various diseases. Using molecular docking and molecular dynamics simulation approaches, we hit three compounds of methyl 4-chloranyl-2-(phenylsulfonyl)-5-sulfamoyl-benzoate (84Z for short), cyclothiazide, and 2,3,5,6-tetrafluoro-4-piperidin-1-ylbenzenesulfonamide (3UG for short) from the existing hCA I inhibitors and word-approved drugs. As a Zn2+-dependent metallo-enzyme, the influence of Zn2+ ion models on the stability of metal-binding sites during MD simulations was addressed as well. MM-PBSA analysis predicted a strong binding affinity of -18, -16, and -14 kcal/mol, respectively, for these compounds, and identified key protein residues for binding. The sulfonamide moiety bound to the Zn2+ ion appeared as an essential component of hCA I inhibitors. Vina software predicted a relatively large (unreasonable) Zn2+-sulfonamide distance, although the relative binding strength was reproduced with good accuracy. The selected compounds displayed potent inhibition against other hCA isoforms of II, XIII, and XIV. This work is valuable for molecular modeling of hCAs and further design of potent inhibitors.

PMID:37628799 | DOI:10.3390/ijms241612619